Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer.

Background: Bavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of ß2 glycoprotein 1 (ß2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and methods: Key eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1 : 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3 mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS). Results: A total of 597 patients were enrolled. Median OS was 10.5 months in the docetaxel + bavituximab arm and was 10.9 months in the docetaxel + placebo arm (HR 1.06; 95% CI 0.88-1.29; P = 0.533). There was no difference in progression-free survival (HR 1.00; 95% CI 0.82-1.22; P = 0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum ß2GP1 levels ≥200 µg/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63-1.06; P = 0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26-0.81; P = 0.006). Conclusions: The combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high ß2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation. Clinical trial number: NCT01999673.

A randomized, double-blind, placebo-controlled, multicenter study of a ginger extract in the management of chemotherapy-induced nausea and vomiting (CINV) in patients receiving high-dose cisplatin.

BACKGROUND: The activity of ginger in the management of chemotherapy-induced nausea and vomiting (CINV) has been suggested, but design inadequacies, heterogeneity of the population, small numbers and poor quality of tested products limit the possibility to offer generalizable results. PATIENTS AND METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter study in patients planned to receive ≥2 chemotherapy cycles with high dose (>50 mg/m2) cisplatin. Patients received ginger 160 mg/day (with standardized dose of bioactive compounds) or placebo in addition to the standard antiemetic prophylaxis for CINV, starting from the day after cisplatin administration. CINV was assessed through daily visual-analogue scale and Functional Living Index Emesis questionnaires. The main objective was protection from delayed nausea; secondary end points included intercycle nausea and nausea anticipatory symptoms. RESULTS: In total, 121 patients received ginger and 123 placebo. Lung (49%) and head and neck cancer (HNC; 35%) were the most represented tumors. No differences were reported in terms of safety profile or compliance. The incidence of delayed, intercycle and anticipatory nausea did not differ between the two arms in the first cycle and second cycle. A benefit of ginger over placebo in Functional Living Index Emesis nausea score differences (day 6-day 1) was identified for females (P = 0.048) and HNC patients (P = 0.038). CONCLUSIONS: In patients treated with high-dose cisplatin, the daily addition of ginger, even if safe, did not result in a protective effect on CINV. The favorable effect observed on nausea in subgroups at particular risk of nausea (females; HNC) deserves specific investigation.

Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial.

BACKGROUND: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy. MATERIALS AND METHODS: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level). RESULTS: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF. CONCLUSIONS: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy. CLINICAL TRIAL NUMBER: NCT01086826, www.clinicaltrials.gov.

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer.

BACKGROUND: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. PATIENTS AND METHODS: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m(2) day 1, LV 100 mg/m(2) as 2 h infusion and 5-FU 400 mg/m(2) as bolus, days 1 and 2 followed by 600 mg/m(2)/day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). RESULTS: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85-1.17; P = 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82-1.18; P = 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. CONCLUSIONS: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01640782.

Targeted therapies and immunotherapy in non-small-cell lung cancer.

Non-small-cell lung cancer is still considered a difficult disease to manage because of its aggressiveness and resistance to common therapies. Chemotherapy remains the gold standard in nearly 80% of lung cancers, but clinical outcomes are discouraging, and the impact on median overall survival (OS) barely reaches 12 months. At the end of the last century, the discovery of oncogene-driven tumours completely changed the therapeutic landscape in lung cancers, harbouring specific gene mutations/translocations. Epidermal growth factors receptor (EGFR) common mutations first and anaplastic lymphoma kinase (ALK) translocations later led new insights in lung cancer biology knowledge. The use of specific tyrosine kinases inhibitors overturned the biological behaviour of EGFR mutation positive tumours and became a preclinical model to understand the heterogeneity of lung cancers and the mechanisms of drug resistance. In this review, we summarise the employment of targeted agents against the most representative biomolecular alterations and provide some criticisms of the therapeutic strategies.

A summary of the Milan experience with multimodality therapies in patients with small cell lung cancer: attempts to improve long-term outcome.

From February 1985 to June 1993, 173 consecutive, previously untreated patients with small cell lung cancer received individualized treatment tailored to disease extent. Almost all patients (14 of 16) with stage I and II disease and 30 patients with operable stage III disease were submitted to surgery preceded or followed by chemotherapy. Chest irradiation and prophylactic brain radiotherapy (in complete responders) were administered at the end of treatment in 42 of 44 cases. Patients with inoperable limited disease received chemotherapy followed by radiotherapy in 67 of 71 cases, while chemotherapy alone or followed by radiotherapy in sites of either initially bulky or residual disease was administered to 58 patients with extensive disease. The overall response rate was 77% (complete response, 45%; partial response, 32%). Complete responses were documented more frequently in limited disease than in extensive disease (57% v 22%; P < .001). The 2- and 5-year freedom from progression rates (24% and 16%, respectively), as well as overall survival rates (31% and 16%, respectively) were significantly affected by disease extent. No patient with extensive disease was progression free and alive at 2 years, while more than half of stage I and II patients were disease free and alive at 5 years. This retrospective analysis performed on a large number of consecutive, nonrandomized patients suggests that, at least in patients with limited disease, it is possible to achieve favorable long-term results using treatment tailored to disease extent. Nonetheless, the disappointing results commonly achieved in the treatment of small cell lung cancer strongly support the need for either prospective, randomized studies to confirm recently reported improved results or new pilot studies with investigation of entirely innovative approaches.

Gene product immunophenotyping of neuroendocrine lung tumors. No linking evidence between carcinoids and small-cell lung carcinomas suggested by multivariate statistical analysis.

Fifty-three neuroendocrine lung tumors (24 carcinoids, one atypical carcinoid, five large-cell neuroendocrine carcinomas, and 23 small-cell lung carcinomas) were investigated for immunocytochemical expression of several gene products, i.e., p53, Rb, bcl-2, c-kit, mdm-2, cdk-4, p21 proteins, and proliferation index as assessed by MIB-1. The goal of the study was to explore the relationships between histotypes in light of their own gene product-based immunophenotypical profiles. To this aim we applied the multiple correspondence analysis, which is an exploratory statistical multivariate technique that converts a data matrix into a particular type of graphic display in which the rows and columns are depicted as points. Such statistical analysis displayed that some categories of the gene product-based immunophenotyping variables are grouped in the plot identifying three groups: the first group related to carcinoids, the second to small-cell carcinomas, and the third to large-cell neuroendocrine carcinomas. These data support the evidence that carcinoids and small-cell carcinomas are two distinct, apparently immunogenotypically unrelated entities among neuroendocrine lung tumors and that atypical carcinoids and large-cell neuroendocrine carcinomas seem not to represent intermediate steps between them.

Comparative in vitro sensitivity of human cholangiocarcinoma and colon adenocarcinoma cells to anticancer agents.

We comparatively investigated the sensitivity of a human cholangiocarcinoma cell line (SG231) and an adenocarcinoma cell line (WiDr) to mitoxantrone (MX), taxol (TX), mitomycin C (MMC), doxorubicin (DX), cisplatin (CDDP) and 5-fluorouracil (5FU) by the sulforhodamine B assay. The lower susceptibility of SG231 to SFU, to CDDP, to DX and to MMC than WiDr was observed, whereas the sensitivity of the two cell lines to MX and TX was similar. We also investigated the ability of a chemical modulator, lonidomine (LND), and hyperthermia to enhance the cytotoxic activity of the different drugs in the SG231 cell line. No potentiation of MX or CDDP activity was observed after a 2 hours treatment in hyperthermic conditions (42 degrees C). Conversely, a slight potentiation of a 2 hours pretreatment with MX and DX was obtained by a 24 hours post treatment with LND.

Chronic effects of subcutaneous interleukin-2 therapy on soluble interleukin-2 receptors in advanced small cell lung cancer.

The increase in IL-2 receptor serum levels is one of the most typical changes in immune parameters during IL-2 cancer immunotherapy. To better define the effects of prolonged IL-2 injection on SIL-2R levels, we evaluated 7 advanced small cell lung cancer patients who received IL-2 subcutaneously at a daily dose of 9 x 10(6) IU/m2/12h for two days followed by 3 x 10(6) IU/m2/12h for 18 days (5 days/week for 4 weeks). Moreover, four patients were also evaluated during the second IL-2 cycle. Venous blood samples were drawn before and at weekly intervals during IL-2 therapy. Mean SIL-2R serum levels rapidly increased with the start of IL-2 injection, and they were significantly higher than the baseline levels throughout the immunotherapy cycle. The increase in mean SIL-2R levels was higher in patients with progressive disease than in those with response or stable disease, but the difference was not significant. Finally, the increase in mean SIL-2R concentrations during the second IL-2 cycle was not significantly different from that seen during the first one. The present study confirms that IL-2 administration determines an evident increase in SIL-2R levels; moreover, it would demonstrate that re-exposure to IL-2 after a rest period does not induce a more pronounced SIL-2R release.

Pilot study with cisplatin, ifosfamide, and etoposide in advanced non-small-cell lung carcinoma.

Twenty-five patients with advanced non-small-cell lung carcinoma (NSCLC) were treated with a multidrug regimen (CIV) consisting of ifosfamide (IFX), cisplatin (CDDP), and etoposide (VP-16). Twenty-four patients were evaluable for response. An objective response was detected in eight cases (33%), including one case with complete tumor response. Median duration of response was 31 weeks, and median overall survival 46 weeks, with no significant difference between responders and nonresponders. Myelosuppression and gastrointestinal side effects represented the main toxic manifestations; a toxic death and an ischemic cardiac episode were also observed. CIV seems a moderately effective regimen in NSCLC, but unlikely to provide an advantage over the widely employed two-drug combination of CDDP and VP-16.

Antiemetic activity of metoclopramide versus alizapride during cancer chemotherapy.

A prospective randomized study was conducted to compare the antiemetic efficacy of metoclopramide (MCP) versus its recent derivative alizapride (ALZ) in patients undergoing cancer chemotherapy. Both drugs were given at a dose of 2 mg/kg i.v. push for 5 doses. A positive response was defined as absence of nausea or emesis, or moderate nausea with one or two emeses per day. Eighty-two patients were evaluable. Forty-two received MCP and 40 received ALZ. A positive response was observed in 54% MCP-treated and 41% ALZ-treated patients. Neurologic toxicity, mainly extrapyramidal disturbances, was the most remarkable adverse side effect; it occurred more frequently in the MCP-treated group (31%) than in the ALZ-treated group (17%). Both drugs were found to be more effective in previously untreated patients and when employed together with steroids. MCP was more effective (52% positive response) than ALZ (41% positive response) in cisplatin-treated patients. To better control drug-induced vomiting, we believe that future trials should evaluate slow i.v. infusion of antiemetic agents and their combination with dexamethasone.

Prognosis after nonradical resections for small cell lung carcinoma (SCLC).

Out of 52 consecutive patients resected for small cell lung carcinoma (SCLC) from 1976 to 1986, 19 were selected because they underwent nonradical surgery, 10 of them for locoregional spread and 9 for distant metastases. Of the former subset all received postoperative radiotherapy and 8 chemotherapy also. Three patients are alive and disease-free 37, 56 and 91 months after resection. Four patients had a distant recurrence, and 3 a locoregional failure. Patients of the latter subgroup received chemotherapy in 7 instances. None survived more than 16 months, distant metastases being the cause of death. In these patients N0 status was associated with 13.3 months of mean survival, N1 with 8.5 months, and N2 with 6.7 months. Surgery and adjuvant treatments seem effective in achieving local control of SCLC despite nonradical resections. Tumor burden at locoregional sites does not preclude the possibility of long term survival.

Pilot study with adriamycin and ifosfamide in small cell lung cancer.

Twenty-one patients with limited (12 cases) or extensive (9 cases) small cell lung cancer entered a pilot study with adriamycin (ADM) plus ifosfamide (IFX) as first line treatment for six planned cycles. ADM was administered at the dose of 60 mg/m2 iv push on day 1 and IFX at 3 g/m2/iv in 1-hour infusion on days 1 and 2. To prevent IFX-induced hemorrhagic cystitis, mercaptoethane sulfonate sodium (Mesna) was given after the administration of IFX at the dose of 500 mg/m2 by iv push four times (hour 0, 4, 8, 12) on days 1 and 2. In the absence of disease progression, chemotherapy was repeated every 3 weeks for 6 cycles. All patients were evaluable for analysis of response, toxicity and survival. The overall response rate clinically and radiologically assessed after four treatment cycles was 95.3% (CR 28.6%, PR 66.7%). However, by continuing the same drug treatment up to the sixth cycle, 7 of 14 partial responders showed tumor progression within the intrathoracic region. Therefore, at the end of the planned chemotherapy program the partial remission rate fell to 33.3%, for a total remission rate of 61.9% and a median total survival of 9 months (range 5 to 36+). The regimen was well tolerated with only one case presenting hemorrhagic cystitis. The results achieved with this drug combination appear comparable to those obtained with other conventional regimens. However, the high response rate achieved after four cycles and the low incidence of marrow toxicity suggest the use of this regimen for a short period with increased dose levels.

Single-agent chemotherapy with vinorelbine for pretreated or metastatic squamous cell carcinoma of the esophagus.

AIMS AND BACKGROUND: At least half of the patients with squamous cell carcinoma of the esophagus (SCCE) present at diagnosis with metastatic disease, and most patients in a locally advanced phase will develop metastases despite potentially curative local therapy. Thus, the majority of patients with SCCE will become candidate for palliative chemotherapy. Only a few drugs have demonstrated moderate activity (>15%) against SCCE. The main purpose of this phase II trial was to assess the activity of vinorelbine, a semisynthetic vinca alkaloid with a wide spectrum of action, in advanced or relapsed SCCE. METHODS: Seventeen patients were included in the trial. Eleven of them had already received chemotherapy (cisplatin and fluorouracil) and/or radiotherapy at the time of the first diagnosis. All patients were treated with vinorelbine at the dose of 30 mg/m2 every two weeks. RESULTS: Sixteen of the 17 patients enrolled in the trial were assessable for activity: partial responses were observed in 4 of the 16 (25%), and 3 of them were pre-treated patients. A significant improvement of dysphagia was obtained in 4 of 11 symptomatic patients. Toxicity was mild, with only one episode of grade 4 neutropenia and constipation. CONCLUSIONS: In our experience, single-agent vinorelbine is active against SCCE. It was also active in patients previously treated with cisplatin and fluorouracil. The good tolerability and the possibility of relieving symptoms such as dysphagia strongly suggest the addition of vinorelbine to combination regimens with cisplatin as front-line chemotherapy for SCCE.

Surgical resection in the treatment of stages I-II of small cell lung carcinoma (SCLC).

From 1981 to 1986, 17 patients with resected small cell lung carcinoma (SCLC) staged as I or II according to the new TNM classification were recruited for a prospective study to evaluate the effectiveness of surgery and postoperative chemotherapy (plus locoregional radiotherapy only when a nonradical resection was accomplished) in the treatment of early stages of the disease. Six patients received full protocol chemotherapy (6 courses) and 8 a mean of 79.1% of the planned courses. Three patients received non adjuvant treatment. Locoregional radiotherapy for residual disease was administered in 2 cases. One patient died for myelosuppression due to chemotherapy and 10 for recurrences of cancer, all within the 20th postoperative month. Metastases accounted 80% of overall recurrences. Six patients were alive and tumor-free at 18, 22, 39, 44, 47 and 51 months from resection. Actuarial observed 3-year survival was 32%.

Nutritional support in patients with cancer of the esophagus: impact on nutritional status, patient compliance to therapy, and survival.

AIMS AND BACKGROUND: The multimodal approach to patients with esophageal squamous cell carcinoma often includes polychemotherapy combined with radiation therapy. Cancer dysphagia and drug-related anorexia, mucositis and vomiting can all lead to malnutrition. The aim of this study was to analyze the impact of the administration of enteral nutrition (EN) on the patient's nutritional status, tolerance of chemotherapy and radiotherapy, and final oncological outcome. METHODS: Fifty esophageal cancer patients who were to be submitted to chemotherapy (days 1-4 5-fluorouracil (FU) 1 g/m2/day and cisplatin (CDDP) 100 mg/m2/day 1) for two cycles plus radiotherapy (31 Gy) were referred to the Nutrition Support Unit prior to any therapy due to their malnourished status. Twenty-nine dysphagic patients received nutrition via tube (37 kcal/kg/day + 2.0 g proteins/kg/day for 34 days), while 21 others who were not dysphagic were given a standard oral diet (SD). The patients who received EN had a more severe weight loss than the SD patients (16.8% vs 12.8%, P <0.02). RESULTS: The dose of administered EN represented 86% of the planned support, and 70% of the nutritional therapy was administered in the home setting. Administration of EN support resulted in stable body weight and unchanged levels of visceral proteins, while SD patients had a decrease in body weight, total proteins and serum albumin (P <0.01). There was no difference between the two groups in terms of tolerance and response to cancer therapy, suitability for radical resection and median survival (9.5 months). CONCLUSIONS: EN in patients with cancer of the esophagus undergoing chemotherapy and radiotherapy is well tolerated, feasible even in the home setting, prevents further nutritional deterioration and achieves the same oncological results in dysphagic patients as those achieved in non-dysphagic patients.

Effect of prolonged subcutaneous administration of interleukin-2 on the circadian rhythms of cortisol and beta-endorphin in advanced small cell lung cancer patients.

Interleukin-2 has been shown to stimulate cortisol secretion in man. Owing to its immunosuppressive properties, an increase in cortisol levels during interleukin-2 cancer immunotherapy could potentially counteract induced activation of the antitumor immune response. Few data are available about cortisol secretion secondary to prolonged interleukin-2 administration. To investigate the problem, we evaluated cortisol circadian rhythms in 7 consecutive metastatic small cell lung cancer patients who received interleukin-2 subcutaneously for 4 weeks (daily dose: 6 x 10(6) x IU/m2). Venous blood samples were drawn at 8.00 a.m., 4.00 p.m. and 12.00 p.m., before interleukin-2, and after each week until the end of the cycle. Beta-endorphin levels were also measured on the same samples. Four patients were evaluated during a second interleukin-2 cycle. Mean cortisol levels increased during interleukin-2 therapy, but were significantly higher than those seen in basal conditions after the first week of treatment. Moreover, cortisol peaks observed during the second cycle of therapy were not significantly different from those seen during the first cycle. Mean beta-endorphin levels increased in response to interleukin-2 administration, but the increase did not reach statistical significance. The early cortisol rise progressively decreased as treatment continued. This suggests that the interleukin-2-induced cortisol rise has no relevant clinical importance in antagonizing the activation of an effective antitumor immune response during cancer immunotherapy with interleukin-2.

[New strategies in the treatment of esophageal cancer]. / Nuove strategie nel trattamento delle neoplasie dell'esofago.

Esophageal cancer is uncommon, but its incidence is rapidly increasing in the Western countries because of the high incidence of the cardia esophageal adenocarcinoma. Notwithstanding the encouraging results achieved with surgical procedures, esophageal carcinoma has a poor prognosis with 5-year survival in 10% of cases without differences between both squamous and adenocarcinoma histologies. Almost 50% of esophageal cancer patients have unresectable disease at presentation; in the past years combined modality treatments, using chemotherapy and/or radiotherapy with or without surgery, have been evaluated to reduce the risk of local and/or distant recurrences. Ongoing regimens with new agents (Taxanes, Vinorelbine, Irinotecan), in association or not with platinum compounds, show good antitumor efficacy and tolerability, even in the metastatic disease. Preoperative strategies with radiation only did not give any advantage compared to surgery alone, instead, controversial results were obtained, with a minimal advantage, using chemotherapy. Combined chemotherapy and radiation, in suitable candidates for resection has shown an improvement of complete pathological responses, in both the histologies, but with superior toxicities when compared to chemotherapy or radiation therapy alone. Postoperative adjuvant therapies as radiation, chemotherapy or both, have not led to a marked improvement in overall survival and should be performed only in clinical trials. The use of chemoradiotherapy showed a clear advantage versus radiotherapy alone and in many cases equivalent to regimens plus surgery even if control studies haven't been performed. Clinical trials with novel biologic agents, in combination to chemotherapy or alone, against cell growth arrest, neoagiongenesis and tumor metastasis invasion process are currently under evaluation. In the coming years new markers as antigen Ki-67 determination, p53 mutation or high levels activity of thymidylate synthase and novel staging techniques as PET could be precious to identify the better treatment for each patient.

Efficacy and Safety of the All-Oral Schedule of Metronomic Vinorelbine and Capecitabine in Locally Advanced or Metastatic Breast Cancer Patients: The Phase I-II VICTOR-1 Study.

Background. Vinorelbine (VRB) and capecitabine (CAPE) are demonstrated to be active in pretreated metastatic breast cancer patients. Different studies have demonstrated that the metronomic treatment is active with an acceptable toxicity profile. We designed a Phases I-II study to define the MTD of oral metronomic, VRB, and CAPE. Patients and Methods. Phase I: fixed dose of CAPE was 500 mg thrice a day, continuously. Level I of VRB was 20 mg/tot thrice a week for 3 weeks (1 cycle). Subsequent levels were 30 mg/tot and 40 mg/tot (Level III), respectively, if no Grades 3-4 toxicity were observed in the previous level. Phase II: further 32 patients received the MTD of VRB plus CAPE for a total of 187 cycles to confirm toxicity profile. Results. 12 patients were enrolled in Phase I and 22 in Phase II. Phase I: the MTD of VRB was 40 mg. Phase II: 187 cycles were delivered, observing 5.9% of Grades 3-4 toxicity. 31 patients are evaluable for efficacy, obtaining a clinical benefit rate of 58.1%. Conclusion. MTD of VRB with fixed dose of CAPE was 40 mg thrice a week and was the recommended dose for the ongoing Phase II multicenter study.